1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether, represented by the chemical formula (CF3)2CH(OCH2F), is generally called “sevoflurane” and is known as an inhalational anesthetic. The production of sevoflurane at low cost is an important issue, and various processes therefor have been researched and developed.
For example, Patent Document 1 listed below discloses a process for producing sevoflurane wherein 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether, obtained by methylation of hexafluoroisopropanol (HFIP), is reacted with chlorine gas to give 1,1,1,3,3,3-hexafluoro-2-propyl chloromethyl ether and this compound is reacted with KF in an organic solvent; a process therefor comprising reacting a 1,1,1,3,3,3-hexafluoro-2-propyl methyl ether with BrF3; and a process therefor comprising reacting HFIP with hydrogen fluoride and formaldehyde.
However, the reaction in which the chloromethyl ether is fluorinated with KF has the drawback of requiring a high temperature and a prolonged reaction, and thus poses problems for implementation on an industrial scale. The process wherein the methyl ether is reacted with BrF3 requires handling of the dangerous BrF3, and is therefore not suitable for mass production. The process wherein HFIP is reacted with hydrogen fluoride and formaldehyde suffers from a low yield due to the formation of a polyether as a by-product.
To overcome these problems, Patent Document 3 listed below, for example, discloses a process wherein hydrogen fluoride and paraformaldehyde are reacted with HFIP in the presence of sulfuric acid. Moreover, Patent Document 2 listed below discloses a process wherein the methyl ether of HFIP is reacted with chlorine gas to produce 1,1,1,3,3,3-hexafluoro-2-propyl chloromethyl ether, which is then reacted with hydrogen fluoride and amine.
With respect to the process wherein hydrogen fluoride and paraformaldehyde are reacted with HFIP in the presence of sulfuric acid, the following inventions have further been made as processes for improving the yield.
For example, Patent Document 4 listed below discloses a process wherein a polyether compound formed as a by-product during the reaction is reacted with hydrogen fluoride and a reaction accelerator such as sulfuric acid or the like to produce Sevoflurane. Patent Document 5 listed below discloses a process wherein hydrogen fluoride and paraformaldehyde are reacted with HFIP in the presence of sulfuric acid, and the formed Sevoflurane is extracted from the equilibrium mixture by distillation or extraction, thereby increasing the yield.
Moreover, Patent Document 6 discloses a process wherein HFIP is reacted with bis(fluoromethyl)ether in the presence of acid.
In addition to the above-described processes, a number of processes for producing Sevoflurane are known, and most of these processes use HFIP as a starting material. As a process for producing HFIP, a process wherein hexafluoroacetone or its hydrate is reduced by hydrogen in the presence of a catalyst (see Patent Documents 7 and 8 listed below, etc.) is known. As processes for producing hexafluoroacetone, a process wherein hexafluoropropylene oxide is rearranged in the presence of a catalyst (Patent Document 9), and a process wherein hexachloroacetone is fluorinated with hydrogen fluoride (Patent Document 10) are known. The former process, however, has a problem in that the starting material, i.e., hexafluoropropylene oxide, is expensive. The latter process also has problems in that the purification processes for separating the resulting hexafluoroacetone from hydrochloric acid, for separating the byproduct chlorofluoroacetone, and the like are complicated, making the process costly.
In view of these circumstances, attempts have been made to produce hexafluoroacetone at low cost. Processes that are attracting attention, in particular, are those using, as starting materials, (CF3)2CHCF2OCH3 (2H-octafluoroisobutyl methyl ether; hereinafter abbreviated to “OIME”) obtained by reacting methanol with octafluoroisobutene which is a by-product of hexafluoropropene that is mass-produced as a monomer for fluororesins, (CF3)2C═CFOCH3 (heptafluoroisobutenyl methyl ether; hereinafter abbreviated to “HIME”) obtained by removing HF from OIME, and the like.
Patent Document 11, for example, discloses a process for producing hexafluoroacetone hydrate, wherein HIME is reacted with oxygen under light irradiation.
Patent Document 12 discloses a process for producing hexafluoroacetone or its hydrate, wherein OIME or HIME is reacted with oxygen in the presence of an activated carbon catalyst.
Patent Document 13 discloses a process for producing hexafluoroacetone, wherein OIME is reacted with triethylamine to give hexafluoroacetone oxime, which is then hydrolyzed with acid.
Patent Document 14 discloses a process for producing hexafluoroacetone hydrate, wherein (CF3)2C(OH)CO2CH3 (methyl 3,3,3-trifluoro-2-trifluoromethyl-2-hydroxypropionate; hereinafter abbreviated to “MTTHP”) is hydrolyzed and then decarboxylated by reacting the hydrolysis product with a halogenating agent.
The process utilizing the photo-oxidation of HINE, however, has problems in that it is difficult to industrially perform light irradiation, and that the yield is low. The oxidation process using an activated carbon catalyst has problems such as inability to perform a long-term operation due to significant degradation of the catalyst, a low selectivity of hexafluoroacetone, and the like. The process wherein OIME is reacted with triethylamine to give an oxime has a problem in that triethylamine, which is an auxiliary starting material, is expensive. The process wherein MTTHP is hydrolyzed and then decarboxylated by halogenation uses an inexpensive auxiliary starting material and has a high yield, but it has the drawback of requiring a large number of steps.
Processes for producing HFIP at low cost without using the intermediate hexafluoroacetone have been contemplated as follows.
For example, Patent Document 15 discloses a process for producing HFIP, comprising synthesizing MTTHP by oxidation of HIME, hydrolyzing the resulting MTTHP, and decarboxylating the hydrolysis product in the presence of a protonic solvent. As a result of re-examination performed by the inventors, however, this process was found to have a low yield because of the formation of CF3(HCF2)C═O (pentafluoroacetone) as a by-product during decarboxylation.
As described above, although the production of hexafluoroacetone or HFIP at low cost is an important issue, satisfactory results have yet to be obtained. Accordingly, in order to produce Sevoflurane at low cost, there is a strong desire for the development of a process for producing hexafluoroacetone or HFIP at low cost, or the development of a process for producing Sevoflurane without using these intermediates.    Patent Document 1: U.S. Pat. No. 3,683,092    Patent Document 2: Japanese Unexamined Patent Publication No. 11-116521    Patent Document 3: U.S. Pat. No. 4,250,334    Patent Document 4: WO 97/30961    Patent Document 5: U.S. Pat. No. 6,469,219    Patent Document 6: U.S. Pat. No. 5,990,359    Patent Document 7: Japanese Examined Patent Publication No. 61-25694    Patent Document 8: Japanese Unexamined Patent Publication No. 6-184025    Patent Document 9: U.S. Pat. No. 3,321,515    Patent Document 10: U.S. Pat. No. 3,544,633    Patent Document 11: Japanese Unexamined Patent Publication No. 61-277645    Patent Document 12: Japanese Unexamined Patent Publication No. 1-203339    Patent Document 13: U.S. Pat. No. 5,466,879    Patent Document 14: Japanese Unexamined Patent Publication No. 2005-306747    Patent Document 15: Japanese Unexamined Patent Publication 2002-234860